tbuckley/cabot-search huggingface dataset:
Abstract IA008: Chromatin regulation by reversible chromatin-associated RNA methylation
Authors: Chuan He
Journal: Cancer Research (2022)

Abstract Over 150 types of post-transcriptional RNA modifications have been identified in all kingdoms of life. We have previously discovered two RNA demethylases, FTO and ALKBH5, which catalyze oxidative demethylation of the most prevalent modifications of mammalian messenger RNA (mRNA) and other nuclear RNA, N6-methyladenosine (m6A). We have also characterized reader proteins that preferentially recognize methylated transcripts to facilitate either decay or translation of these target RNAs. Most recently we have discovered m6A methylation of chromatin-associated regulatory RNAs (carRNAs), which modulates chromatin state and transcription in mouse embryonic stem cells (mESCs). These findings suggest that reversible RNA modification could impact chromatin regulation analogous to the reversible DNA and histone chemical modifications. I will present recent mechanistic investigation of chromatin and transcription regulation through m6A methylation and demethylation, and impacts on mammalian development and cancer progression. Citation Format: Chuan He. Chromatin regulation by reversible chromatin-associated RNA methylation. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA008.
Abstract B017: Dysregulation of ultra long-range DNA methylation canyon interactions in human acute myeloid leukemia
Authors: Xue Qing D. Wang, Fan Feng, Yali Dou, Jie Liu, Xiaotian Zhang
Journal: Cancer Research (2022)

Abstract DNA methylation Canyons (DMCs) are genomic regions devoid of DNA methylation over 3.5kb in hematopoietic stem cells (HSCs). DMCs form ultra long-range interactions spanning decades of megabases specifically in HSCs. These ultra-long DMC interactions between DMCs relies on the strong Polycomb binding inside DMC regions. DMCs are hypermethylated and partially activated in cancer. However, its 3D genomic alterations have not been examined extensively. Here we profiled the high-resolution 3D genomic interactions in 7 primary human acute myeloid leukemia (AMLs). Focusing on DMCs' epigenome state, we found that DMCs in all AMLs are hypermethylated and lose the strong Polycomb enrichment within DMCs in comparison with HSC. Based on the DMC interactions, we discovered two subtypes of AMLs with distinct 3D genomic dysregulation of DMCs’ long-range interactions. In the first AML subtype, DMCs’ interactions are still strong as HSPC but gained leukemia-specific long-range interactions. This subtype is enriched for WT1 mutations and is characterized by the expression of CD34 on blast cells. This particular subtype displayed a global basal level increase in the H3K27me3 mark in the genome. This particular subtype of AML is also sensitive to the EZH2 inhibitor treatment. The EZH2 inhibitor treatment leads to the differentiation of blasts and reduces the colony-forming ability of this subtype of AML. Further dissection shows the EZH2 inhibitors could eradicate the leukemia-specific ultra-long range interactions. In the second subtype of AML, 3D genomic interactions between DMCs significantly lost in AMLs with high HOX cluster gene expression (MLL-r and NPM1c+ AMLs). We further found repressive DMC genes, which are developmental transcriptional factors(TFs) in organ formation are activated in these AMLs. Interestingly, these developmental TFs are involved in forming leukemia-specific long-range interactions independent of CTCF-mediated TADs and chromosomal loops. Among those TFs, IRX3 and IRX5 are frequently activated in MLL-r, NPM1c+ AML and MPAL. These two genes have also been shown before to immortalize bone marrow progenitor cells and block differentiation of these progenitor cells. The loci of these two genes form strong long-range connections to an upstream FTO enhancer mimicking the 3D genomic structure observed in developing muscle and brains. Citation Format: Xue Qing D. Wang, Fan Feng, Yali Dou, Jie Liu, Xiaotian Zhang. Dysregulation of ultra long-range DNA methylation canyon interactions in human acute myeloid leukemia. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B017.
Abstract A027: Identification and role of mega-trans-factors in epithelial ovarian cancer
Authors: Sushil Kumar Jaiswal, Kevin Fedkenheuer, Laura Elnitski
Journal: Cancer Research (2022)

Abstract Epithelial ovarian cancer (EOC) accounts for over 90% of ovarian cancer cases and results in 14,000 U.S. deaths annually. It is the leading cause of death attributed to gynecological cancers. Aside from recent scientific advances, the 5-year survival rate for late-stage invasive EOC has been near 30% for several decades. Our computational transcriptional regulatory analysis in low-grade serous ovarian cancers (LGSOCs) vs. high-grade serous ovarian cancers (HGSOCs) identified a master regulatory complex, Megatrans complex (MTC), the objective of this study is to identify role of MTC in ovarian cancer, never reported before. MTC is estrogen-responsive master regulatory complex containing a multitude of DNA-binding transcription factors (MTC_TFs), including ER-alpha, RAR-alpha, GATA3, AP2-gamma, STAT1, AP1, RUNX1, and FOXA1. Given that we found MTC gene targets are downregulated in HGSOC, and that some target genes are prognostic for poor patient survival, understanding the function of MTC and modulating its activity may improve prognostic outcomes for HGSOC patients. We hypothesize that different combinations of MTC_TFs produce distinct regulatory signatures in different grades of ovarian cancers. In the grade, PEO4, cell line, we have confirmed MTC formation using a gel filtration assay and identified the presence of MTC_TFs by western blot. We discovered tumor suppressor, PITX1, as a novel MTC_TF in ovarian cancer, not previously reported in a breast cancer MTC. Methylation analysis revealed PITX1 and ER-alpha binding to hypomethylated, but repressed promoters and ChIP-seq analysis revealed PITX1 co-occupying 98.8% of ER-alpha binding sites, suggesting a repressive role of PITX1 on ER-alpha regulated genes. We are performing additional ChIP-seq experiments of MTC_TFs in HGSOC and LGSOC cell lines to test whether the MTC_TF binding distinguishes their regulatory signatures. Our findings of a nuclear hormone-regulated MTC complex controlling the transcriptional landscape of ovarian cancer are expected to facilitate new breakthroughs in disease treatment. Citation Format: Sushil Kumar Jaiswal, Kevin Fedkenheuer, Laura Elnitski. Identification and role of mega-trans-factors in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A027.
Non-invasive biomarkers for liver inflammation in non-alcoholic fatty liver disease: present and future
Authors: Terry Cheuk-Fung Yip, Fei Lyu, Huapeng Lin, Guanlin Li, Pong-Chi Yuen, Vincent Wai-Sun Wong, Grace Lai-Hung Wong
Journal: Clinical and Molecular Hepatology (2022)

Inflammation is the key driver of liver fibrosis progression in non-alcoholic fatty liver disease (NAFLD). Unfortunately, it is often challenging to assess inflammation in NAFLD due to its dynamic nature and poor correlation with liver biochemical markers. Liver histology keeps its role as the standard tool, yet it is well-known for substantial sampling, intraobserver, and interobserver variability. Serum proinflammatory cytokines and apoptotic markers, namely cytokeratin-18, are well-studied with reasonable accuracy, whereas serum metabolomics and lipidomics have been adopted in some commercially available diagnostic models. Ultrasound and computed tomography imaging techniques are attractive due to their wide availability; yet their accuracies may not be comparable with magnetic resonance imaging-based tools. Machine learning and deep learning models, be they supervised or unsupervised learning, are promising tools to identify various subtypes of NAFLD, including those with dominating liver inflammation, contributing to sustainable care pathways for NAFLD.
Novel Cardiokine GDF3 Predicts Adverse Fibrotic Remodeling After Myocardial Infarction
Authors: Nihar Masurkar, Marion Bouvet, Damien Logeart, Charlène Jouve, Fatou Dramé, Olivier Claude, Maguelonne Roux, Clément Delacroix, Damien Bergerot, Jean-Jacques Mercadier, Marc Sirol, Barnabas Gellen, Marine Livrozet, Antoine Fayol, Estelle Robidel, David-Alexandre Trégouët, Giovanna Marazzi, David Sassoon, Mariana Valente, Jean-Sébastien Hulot
Journal: Circulation (2022)

Myocardial infarction (MI) induces a repair response that ultimately generates a stable fibrotic scar. Although the scar prevents cardiac rupture, an excessive profibrotic response impairs optimal recovery by promoting the development of noncontractile fibrotic areas. The mechanisms that lead to cardiac fibrosis are diverse and incompletely characterized. We explored whether the expansion of cardiac fibroblasts after MI can be regulated through a paracrine action of cardiac stromal cells.We performed a bioinformatic secretome analysis of cardiac stromal PW1+ cells isolated from normal and post-MI mouse hearts to identify novel secreted proteins. Functional assays were used to screen secreted proteins that promote fibroblast proliferation. The expressions of candidates were subsequently analyzed in mouse and human hearts and plasmas. The relationship between levels of circulating protein candidates and adverse post-MI cardiac remodeling was examined in a cohort of 80 patients with a first ST-segment-elevation MI and serial cardiac magnetic resonance imaging evaluations.Cardiac stromal PW1+ cells undergo a change in paracrine behavior after MI, and the conditioned media from these cells induced a significant increase in the proliferation of fibroblasts. We identified a total of 12 candidates as secreted proteins overexpressed by cardiac PW1+ cells after MI. Among these factors, GDF3 (growth differentiation factor 3), a member of the TGF-β (transforming growth factor-β) family, was markedly upregulated in the ischemic hearts. Conditioned media specifically enriched with GDF3 induced fibroblast proliferation at a high level by stimulation of activin-receptor-like kinases. In line with the secretory nature of this protein, we next found that GDF3 can be detected in mice and human plasma samples, with a significant increase in the days after MI. In humans, higher GDF3 circulating levels (measured in the plasma at day 4 after MI) were significantly associated with an increased risk of adverse remodeling 6 months after MI (adjusted odds ratio, 1.76 [1.03-3.00]; P=0.037), including lower left ventricular ejection fraction and a higher proportion of akinetic segments.Our findings define a mechanism for the profibrotic action of cardiac stromal cells through secreted cardiokines, such as GDF3, a candidate marker of adverse fibrotic remodeling after MI.URL: https://www.gov; Unique identifier: NCT01113268.
Contextual Considerations When Interpreting Well-Child Visit Adherence Results—Reply
Authors: Salam Abdus, Thomas M. Selden
Journal: JAMA Pediatrics (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Psychological Interventions for Adult Post-Traumatic Stress Disorder Are Effective Irrespective of Concurrent Psychotropic Medication Intake: A Meta-Analysis of Randomized Controlled Trials
Authors: Thole H. Hoppen, Nexhmedin Morina
Journal: Psychotherapy and Psychosomatics (2022)

Background: Participants are allowed to stay on their prescribed psychotropic medication in most trials examining psychological interventions for adult post-traumatic stress disorder (PTSD). Objectives: We aimed to conduct the first meta-analysis investigating the potential influence of such concurrent medication on efficacy. Method: To this end, we searched Medline, PsycINFO, Web of Science, and PTSDpubs from inception to April 21, 2022, for trials meeting the following criteria: (1) randomized controlled trial (RCT), (2) PTSD as primary treatment focus, (3) interview-based PTSD baseline rate ≥70%, (4) N ≥ 20, (5) mean age ≥18 years. Trials were excluded when intake of psychotropics was not (sufficiently) reported. Results: Most published trials did not report on the intake of psychotropic medication. A total of 75 RCTs (N = 4,901 patients) met inclusion criteria. Trauma-focused cognitive behavior therapy (TF-CBT) was the most well-researched intervention. Short-term efficacy of psychological treatments did not differ by the proportion of participants taking concurrent psychotropic medication during psychological treatment in all but one analysis. In trials comparing TF-CBT and active control conditions at posttreatment, TF-CBT was more effective when most participants were concurrently medicated (g = 0.87, 95% CI 0.53–1.22) rather than unmedicated (g = 0.27; 95% CI 0.01–0.54, p = 0.017), with younger age (b1 = −0.04, p = 0.008) and higher proportion of females (b1 = 0.01, p = 0.014) being associated with higher efficacy only in trials with high proportions of medicated participants. No differences in efficacy by proportions of participants taking concurrent psychotropic medication were found at follow-up. Conclusions: Results suggest that psychological interventions are effective for PTSD irrespective of concurrent intake of psychotropics.
Epistemic Rights and Responsibilities of Digital Simulacra for Biomedicine
Authors: Mildred K. Cho, Nicole Martinez-Martin
Journal: The American Journal of Bioethics (2022)

Big data and AI have enabled digital simulation for prediction of future health states or behaviors of specific individuals, populations or humans in general. "Digital simulacra" use multimodal datasets to develop computational models that are virtual representations of people or groups, generating predictions of how systems evolve and react to interventions over time. These include digital twins and virtual patients for
Association Between County-Level Natality and Income in the US, 2000-2020
Authors: Nick Turner, Kendra Robbins
Journal: JAMA Pediatrics (2022)

It is generally accepted that birth rates are negatively associated with income. However, less is known about the nature and evolution of natality differences between high- and low-income counties and how these differences are associated with the recent decline in the birth rate overall in the US.
Error in Table
Journal: JAMA Neurology (2022)

Kazutaka Uchida, MD, PhD; Seigo Shindo, MD, PhD; Shinichi Yoshimura, MD, PhD; Kazunori Toyoda, MD, PhD; Nobuyuki Sakai, MD, PhD; Hiroshi Yamagami, MD, PhD; Yuji Matsumaru, MD, PhD; Yasushi Matsumoto, MD; Kazumi Kimura, MD, PhD; Reiichi Ishikura, MD, PhD; Astushi Yoshida, MD, PhD; Manabu Inoue, MD, PhD; Mikiya Beppu, MD, PhD; Fumihiro Sakakibara, MD; Manabu Shirakawa, MD, PhD; Takeshi Morimoto, MD, PhD, MPH; RESCUE-Japan LIMIT Investigators; Naoya Kuwayama; Kuniaki Ogasawara; Teruyuki Hirano; Norito Kinjo; Takuya Saito; Masataka Takeuchi; Yukako Yazawa; Naoto Kimura; Keigo Shigeta; Hirotoshi Imamura; Ichiro Suzuki; Yukiko Enomoto; So Tokunaga; Kenichi Morita; Kanta Tanaka; Ryuzaburo Kanazawa; Takumi Asai; Norihito Shimamura; Hideyuki Ishihara; Masafumi Morimoto; Hiroyuki Ohnishi; Yoshinori Akiyama; Nobuhisa Matsushita; Nobuaki Yamamoto; Koichi Haraguchi; Hayato Araki; Atsushi Ogata; Hirotaka Okumura; Tatsuya Ogino; Yoshitaka Yamada; Takahiro Ota; Yoshifumi Tsuboi; Takehiro Yamada; Manabu Nagata; Kenichi Todo; Fuminori Shimizu; Yasushi Ueno; Masataka Yoshimura; Wataro Tsuruta; Yoichi Morofuji; Naoki Toma; Tomoya Omae; Makoto Sakamoto; Toshihiro Ueda; Shinya Koyama
Noninvasive imaging biomarkers for liver fibrosis in nonalcoholic fatty liver disease: current and future
Authors: Jung Hwan Yu, Han Ah Lee, Seung Up Kim
Journal: Clinical and Molecular Hepatology (2022)

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide and becoming a major cause of liver disease-related morbidity and mortality. The presence of liver fibrosis in patients with NAFLD is closely related to prognosis, including the development of hepatocellular carcinoma and other complications of cirrhosis. Therefore, assessment of the presence of significant or advanced liver fibrosis is crucial. Although liver biopsy has been considered the “gold standard” method for evaluating the degree of liver fibrosis, it is not suitable for extensive use in all patients with NAFLD owing to its invasiveness and high cost. Therefore, noninvasive biochemical and imaging biomarkers have been developed to overcome the limitations of liver biopsy. Imaging biomarkers for the stratification of liver fibrosis have been evaluated in patients with NAFLD using different imaging techniques, such as transient elastography, shear wave elastography, and magnetic resonance elastography. Furthermore, artificial intelligence and deep learning methods are increasingly being applied to improve the diagnostic accuracy of imaging techniques and overcome the pitfalls of existing imaging biomarkers. In this review, we describe the usefulness and future prospects of noninvasive imaging biomarkers that have been studied and used to evaluate the degree of liver fibrosis in patients with NAFLD.
Diselenide‐Based Dual‐Responsive Prodrug as Pyroptosis Inducer Potentiates Cancer Immunotherapy
Authors: Shu‐Cheng Wan, Meng‐Jie Ye, Qi‐Chao Yang, Tian Zhang, Meng‐Jie Zhang, Xian‐Bin Ma, Ji‐Ming Xu, Shuo Wang, Zhi‐Zhong Wu, Lei‐Lei Yang, Xue‐Meng Shen, Zhigang Xu, Zhi‐Jun Sun
Journal: Advanced Healthcare Materials (2022)

Abstract Pyroptosis is demonstrated to trigger antitumor immunity and represents a promising new strategy to potentiate cancer immunotherapy. The number of potent pyroptosis inducers, however, is limited and without tumor‐targeting capability, which inevitably causes damage in normal tissues. Herein, a small molecular prodrug of paclitaxel‐oxaliplatin is rationally synthesized, which can be covalently self‐assembled with diselenide‐containing cross‐linking (Dse11), producing a diselenide nanoprodrug (DSe@POC) to induce pyroptosis for the first time. The diselenide bonds within DSe@POC can be split by high glutathione in the tumor microenvironment (TME) and reactive oxygen species induced by photodynamic therapy, thus possessing excellent TME on‐target effects. Additionally, DSe@POC is able to elicit intense pyroptosis to remodel the immunostimulated TME and trigger a robust immune response. Furthermore, combined α PD‐1 therapy effectively inhibits the growth of remote tumors through the abscopal effect, amplifies a long‐term immune memory response to reject rechallenged tumors, and prolongs survival. Collectively, DSe@POC, as the first TME dual‐responsive diselenide‐based pyroptosis inducer, will open up an attractive approach for cancer immunotherapy.
Nivolumab and Doxorubicin, Vinblastine, and Dacarbazine in Early-Stage Unfavorable Hodgkin Lymphoma: Final Analysis of the Randomized German Hodgkin Study Group Phase II NIVAHL Trial
Authors: Paul J. Bröckelmann, Ina Bühnen, Julia Meissner, Karolin Trautmann-Grill, Peter Herhaus, Teresa V. Halbsguth, Valdete Schaub, Andrea Kerkhoff, Stephan Mathas, Matthias Bormann, Andreas Dickhut, Helen Kaul, Michael Fuchs, Carsten Kobe, Christian Baues, Peter Borchmann, Andreas Engert, Bastian von Tresckow
Journal: Journal of Clinical Oncology (2022)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the investigator-sponsored randomized phase II NIVAHL trial for early-stage unfavorable classical Hodgkin lymphoma (HL), two schedules of four cycles of nivolumab, doxorubicin, vinblastine, and dacarbazine followed by 30 Gy involved-site radiotherapy resulted in high complete remission rates and an unprecedented 1-year progression-free survival in 109 patients. In this article, we report the preplanned final analysis conducted three years after the registration of the last patient including long-term safety results. No survival events were observed since the primary analysis, and after a median follow-up (FU) of 41 months, the overall survival was 100% in both treatment groups. The progression-free survival was 98% and 100% in the sequential and concomitant nivolumab, doxorubicin, vinblastine, and dacarbazine treatment groups, respectively. At last FU, the mean forced expiratory pressure in one second was 95.5% (standard deviation 12.7%), the mean diffusion capacity for carbon monoxide adjusted for hemoglobin was 82.8% (standard deviation 15.4%), and the left ventricular ejection fraction was in the normal range in 95% of patients. Hypothyroidism requiring long-term medication occurred in 15% of patients, who were nearly exclusively female (87%). No second primary malignancies occurred, and no patient required corticosteroid treatment at last FU. Patient-reported normalized global quality-of-life score measured by European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 improved over time. This preplanned FU analysis of the largest anti-programmed death protein 1 HL first-line trial to date confirms the outstanding efficacy and relatively favorable safety profile of this therapeutic approach.